The present invention is directed to the synthesis of iron-saccharidic complexes comprising an active hematinic species suitable for medicinal use, e.g., for parenteral administration of a composition comprising such a complex to a human or an animal in need thereof. Iron deficiency can develop from many conditions or disorders, including those linked to renal disease, repeated kidney dialysis, and cancer treatment wherein low hematocrit levels may require erythropoietin treatment in combination with iron supplements. Other routes that compromise heme synthesis are known as well. Currently available iron supplements in a form suitable for parenteral administration to treat iron deficiency, include, for example, dextran and non-dextran containing compositions.
The non-dextran iron-containing complexes or compounds (iron-saccharidic complexes) disclosed in patent and journal literature typically have a relatively low molecular weight, e.g., up to about 2500 Daltons or less. Many of these low molecular weight compounds are suited only for oral administration, not parenteral therapeutic use (See, e.g., Montgomery et al., U.S. Pat. No. 3,821,192; Rao et al. “Fe(III) Complexes of D-Glucose and D-Fructose,” Biometals, vol. 7, pp. 25-29, 1994; Geetha et al. “Transition-metal Saccharide Chemistry: Synthesis, Spectroscopy, Electrochemistry and Magnetic Susceptibility Studies of Iron(III) Complexes of Mono- and Disaccharides,” Carbohydrate Research, vol. 271, pp. 163-175, 1995; Rao et al. “Solution Stability of Iron-Saccharide Complexes,” Bioorganic and Medicinal Chemistry Letters, vol. 2, No. 9, pp. 997-1002, 1992; Rao et al. “Transition Metal Saccharide Chemistry and Biology: Syntheses, Characterization, Solution Stability and Putative Bio-relevant Studies of Iron-Saccharide Complexes,” Inorganica Chimica Acta, vol. 297, pp. 373-382, January 2000; Burger et al. “A Novel Polynuclear Iron (III) Mixed Ligand Complex for Use in Parenteral Iron Therapy,” Inorganica Chimica Acta, Vol. 80, pp. 231-235, 1983). Hematinic products based on polymeric saccharides or polysaccharides such as starch, cellulose, dextran and dextrin are not useful in the present invention. In particular, dextran and dextrin polysaccharides can have molecular weights of about 40,000 to about 75,000 or more.
A non-dextran iron-saccharidic complex is commercially available, for example, under the tradename “Ferrlecit” (Watson Pharmaceuticals, Inc.); the product is identified as sodium ferric gluconate complex in sucrose (SFGCS). The manufacturer states that the structural formula of the product is considered to be [NaFe2O3(C6H11O7) (C12H22O11)5]n, where n is about 200, and as having an apparent molecular weight of 289,000-440,000 Daltons; based on the above structural formula, the formula weight is 417,600. The commercial hematinic composition is further described as the sodium salt of a ferric ion carbohydrate complex in an alkaline aqueous solution with approximately 20% sucrose, wt./vol. (195 mg/mL) in water, pH 7.7-9.7.
Another commercially available, non-dextran hematinic, marketed under the tradename “Venofer” (American Regent Laboratories, Inc.), is compositionally described as ferric hydroxide-sucrose complex (FHSC). The descriptive name suggests a form of ferric iron, i.e. Fe (III), that is present in a complex with sucrose.
Interestingly, synthetic routes for preparing commercially available parenteral hematinics, including those useful for treating humans, are believed to be unknown in the literature and the molecular structures of the resulting hematinics are poorly characterized. Only recently has a method for obtaining accurate reference standards been published (See U.S. Pat. No. 6,537,820, R. A. Beck and R. A. Mateer, Jr.; assigned to Chromaceutical Advanced Technologies, Inc.).
Iron-saccharidic complexes with hematinic activity generally contain iron atoms as Fe(III) (i.e., iron in the ferric valence state) which is believed to be necessary for hematopoiesis. Additionally, such complexes will include Fe(III) as part of a high molecular weight structure which is necessary in order to be useful for parenteral administration in humans. Iron-saccharidic complexes should be capable of delivering therapeutically useful iron for hematopoiesis over an extended period of time, e.g., for at least one day after administration and preferably over a period of several days after administration. However, localized administration of highly concentrated iron in the form of low molecular weight iron-saccharidic compounds or complexes are not subject to slow release and may produce adverse side effects, including toxicity. Such effects may be exhibited as localized damage at an injection site or unpredictable systemic responses in humans or animals in the form of shock, anaphylaxis, vascular hypotension, lethality or other indications of intolerance to the drug.
There is a continuing need in the field of therapeutic parenteral iron supplements for a well-defined synthesis method to which modern control and analytical methods can be applied and compositions produced thereby. Such an improved process can facilitate the manufacture of a product having enhanced purity. The present invention relates to the preparation or synthesis of therapeutically active iron-containing compounds and compositions, particularly useful in compositions comprising parenteral hematinic pharmaceuticals. Unique iron complexes are also described.